Claudia Beisel

Decreased frequency of CD73+CD8+ T cells of HIV-infected patients correlates with immune activation and T cell exhaustion

Recent studies indicate that murine Tregs highly express the ENTDP1, as well as the 5′‐NT and thereby, suppress Teff function by extracellular adenosine production. Furthermore, CD73 seems to play a role as costimulatory molecule for T cell differentiation. In this study, we analyzed the expression of CD73 on peripheral and lymph nodal Teffs and Tregs in a cohort of 95 HIV patients at different stages of disease, including LTNP and ECs. In contrast to murine Tregs, CD73 was only expressed on a small minority (∼10%) of peripheral Tregs. In contrast, we see high expression of CD73 on peripheral CD8+ T cells. In HIV infection, CD73 is markedly reduced on all Teffs and Tregs, regardless of the memory subtype. On CD8+ T cells, a positive correlation between CD73 expression and CD4 counts (P=0.0003) was detected. CD73 expression on CD8+ T cells negatively correlated with HLA‐DR (<0.0001) and PD1 (P=0.0457) expression. The lower CD73 expression on CD8+ T cells was partially reversible after initiation of ART (P=0.0016). Functionally, we observed that CD8+CD73+ T cells produce more IL‐2 upon HIV‐specific and unspecific stimulation than their CD73− counterparts and show a higher proliferative capacity. These data indicate that down‐regulation of CD73 on CD8+ T cells correlates with immune activation and leads to functional deficits in HIV infection.

Association of autoimmune hepatitis and systemic lupus erythematodes: A case series and review of the literature

Liver test abnormalities have been described in up to 60% of patients with systemic lupus erythematodes (SLE) at some point during the course of their disease. Prior treatment with potentially hepatotoxic drugs or viral hepatitis is commonly considered to be the main cause of liver disease in SLE patients. However, in rare cases elevated liver enzymes may be due to concurrent autoimmune hepatitis (AIH). To distinguish whether the patient has primary liver disease with associated autoimmune clinical and laboratory features resembling SLE - such as AIH - or the elevation of liver enzymes is a manifestation of SLE remains a difficult challenge for the treating physician. Here, we present six female patients with complex autoimmune disorders and hepatitis. Patient charts were reviewed in order to investigate the complex relationship between SLE and AIH. All patients had coexisting autoimmune disease in their medical history. At the time of diagnosis of AIH, patients presented with arthralgia, abdominal complaints, cutaneous involvement and fatigue as common symptoms. All patients fulfilled the current diagnostic criteria of both, AIH and SLE. Remission of acute hepatitis was achieved in all cases after the initiation of immunosuppressive therapy. In addition to this case study a literature review was conducted.

German cohort of HCV mono-infected and HCV/HIV co-infected patients reveals relative under-treatment of co-infected patients

BackgroundCurrent German and European HIV guidelines recommend early evaluation of HCV treatment in all HIV/HCV co-infected patients. However, there are still considerable barriers to initiate HCV therapy in everyday clinical practice. This study evaluates baseline characteristics, “intention-to-treat” pattern and outcome of therapy of HCV/HIV co-infected patients in direct comparison to HCV mono-infected patients in a “real-life” setting.MethodsA large, single-center cohort of 172 unselected HCV patients seen at the Infectious Diseases Unit at the University Medical Center Hamburg-Eppendorf from 2000–2011, 88 of whom HCV/HIV co-infected, was retrospectively analyzed by chart review with special focus on demographic, clinical and virologic aspects as well as treatment outcome.ResultsAntiviral HCV combination therapy with PEG-interferon plus weight-adapted ribavirin was initiated in 88/172 (52%) patients of the entire cohort and in n = 36 (40%) of all HCV/HIV co-infected patients (group A) compared to n = 52 (61%) of the HCV mono-infected group (group B) (p = 0.006). There were no significant differences of the demographics or severity of the liver disease between the two groups with the exception of slightly higher baseline viral loads in group A. A sustained virologic response (SVR) was observed in 50% (n = 18) of all treated HIV/HCV co-infected patients versus 52% (n = 27) of all treated HCV mono-infected patients (p = 0.859). Genotype 1 was the most frequent genotype in both groups (group A: n = 37, group B: n = 49) and the SVR rates for these patients were only slightly lower in the group of co-infected patients (group A: n = 33%, group B: 40% p = 0.626). During the course of treatment HCV/HIV co-infected patients received less ribavirin than mono-infected patients.ConclusionOverall, treatment was only initiated in half of the patients of the entire cohort and in an even smaller proportion of HCV/HIV co-infected patients despite comparable outcome (SVR) and similar baseline characteristics. In the light of newer treatment options, greater efforts to remove the barriers to treatment that still exist for a great proportion of patients especially with HIV/HCV co-infection have to be undertaken.

Human pDCs display sex-specific differences in type I interferon subtypes and interferon α/β receptor expression

The outcomes of many diseases differ between women and men, with women experiencing a higher incidence and more severe pathogenesis of autoimmune and some infectious diseases. It has been suggested that this is partially due to activation of plasmacytoid dendritic cells (pDCs), the main producers of interferon (IFN)‐α, in response to toll‐like receptor (TLR)7 stimulation. We investigated the induction of type I IFN (IFN‐I) subtypes upon TLR7 stimulation on isolated pDCs. Our data revealed a sex‐specific differential expression of IFN‐Is, with pDCs from females showing a significantly higher mRNA expression of all 13 IFN‐α subtypes. In addition, pDCs from females had higher levels of IFN‐β mRNA after stimulation, indicating that sex differences in IFN‐I production by pDCs were mediated by a signaling event upstream of the first loop of IFN‐I mRNA transcription. Furthermore, the surface expression levels of the common IFN‐α/β receptor subunit 2 were significantly higher on pDCs from females in comparison to males. These data indicate that higher IFN‐α production is already established at the mRNA level and propose a contribution of higher IFN‐α/β receptor 2 expression on pDCs to the immunological differences in IFN‐I production observed between females and males.

Down‐regulation of CD73 on B cells of patients with viremic HIV correlates with B cell activation and disease progression

Recently, alterations of the T cell expression of the ectonucleotidases, CD39 and CD73, during HIV infection have been described. Here, peripheral (n = 70) and lymph nodal B cells (n = 10) of patients with HIV at different stages of disease as well as uninfected individuals were analyzed via multicolor flow cytometry with regard to expression of CD39 and CD73 and differentiation, proliferation, and exhaustion status. Patients with chronic, untreated HIV showed a significantly decreased frequency of CD73‐expressing B cells (P < 0.001) compared with healthy controls. Decreased frequencies of CD39+CD73+ B cells in patients with HIV correlated with low CD4+ counts (P < 0.0256) as well as increased proliferation and exhaustion status as determined by Ki‐67 and programmed death‐1 expression. Down‐regulation of CD73 was observed in naive and memory B cells as determined by CD27 and CD21. Neither HIV elite controller patients nor antiretroviral therapy–treated patients had significantly lower CD39 and CD73 expression on B cells compared with healthy controls. Of importance, low CD73+ expression on B cells was associated with modulated in vitro B cell function. Further in vivo studies are warranted to evaluate the in vivo role of phenotypic loss of CD73 in B cell dysregulation in HIV.

Infections complicating severe alcoholic hepatitis: Enterococcus species represent the most frequently identified pathogen.

Abstract Background: Patients with acute alcoholic steatohepatitis are at a high risk for infections. To date, neither disease-specific pathogen patterns, nor typical sites of infection, nor antibiotic treatment strategies have been established for AH. Aims: To characterize incidence of infections, pathogen spectrum, sites of infection, and related mortality of patients with AH under steroid therapy. Methods: We retrospectively analyzed clinical data of 73 patients with severe alcoholic hepatitis (MELD ≥ 20). Results: Infections were detected in 45 patients (73%). Patients who developed an infection after initiation of corticosteroid therapy had a higher 6-month mortality than patients without onset of infection after initiation of corticosteroid treatment (44% versus 24%, p = 0.116). The pathogen identified most frequently was Enterococcus species. Discussion: Infections frequently complicate severe alcoholic hepatitis and affect survival. The high rate of Enterococcus infections suggests that commonly used antibiotics, such as cephalosporins and quinolones, may represent an ineffective choice of empiric antibiotic treatment for complicated AH.

TLR7-mediated activation of XBP1 correlates with the IFNα production in humans

HighlightsSignaling via TLR7 leads to an upregulation of the transcription factor XBP1 in PBMCs and pDCs.XBP1 mRNA expression levels positively correlated with the subsequent production of IFN&agr;.Blocking of XBP1 mRNA splicing significantly reduced mRNA transcripts of IFN&agr;.Our data demonstrate a central role of XBP1 in TLR7‐induced IFN&agr; production.XBP1 represents a potential therapeutic target in IFN&agr;‐driven autoimmune and inflammatory diseases. ABSTRACT The transcription factor X‐box binding protein 1 (XBP1) represents a key component of the endoplasmatic reticulum (ER) stress response and is required for the production of several pro‐inflammatory cytokines. XBP1 is furthermore essential for the development and survival of plasmacytoid dendritic cells (pDCs), and has recently been suggested to be involved in toll‐like receptor (TLR) 2/4 signaling. Activation of TLR7 on pDCs results in an upregulation of pro‐inflammatory cytokines, such as type I interferons (IFN‐I), and has been implicated in several autoimmune and inflammatory diseases, but the role of XBP1 in this process remains unknown. Here, we show that signaling via TLR7 leads to an upregulation of XBP1 and IFN&agr;‐production. XBP1 mRNA expression levels positively correlated with the production of IFN&agr;, while blocking of XBP1 mRNA splicing significantly reduced mRNA transcripts of IFN&agr;. In conclusion, these data suggest a central role of XBP1 in TLR7‐induced IFN&agr; production and identify XBP1 as a potential novel therapeutic target in IFN&agr;‐driven autoimmune and inflammatory diseases.

Geschlechtsunterschiede bei Infektionserkrankungen

Differences between women and men range from their anatomy, their natural social behavior to their susceptibility and response to different pathologies, including infectious diseases. The underlying mechanisms of sex differences in infectious diseases are manifold, including differences in exposure to common pathogens, genetic factors that modulate immune responses against pathogens and hormonal factors that may alter susceptibility or disease progression, and responsiveness to treatment. On one hand, these mechanisms lead to higher innate and adaptive immune responses in females, which result in faster clearance of acute infections and higher antibody responses to several vaccines, on the other hand this contributes to an increased susceptibility to chronic inflammatory diseases. In this review we summarize the underlying causes of sex differences in prevalence, clinical course of disease and treatment outcome of infectious diseases. In order to develop individualized treatment concepts, a fair balance between the sexes should be maintained in basic science, preclinical and clinical studies.